The goal of this Mid-Career Investigator Award in patient-oriented research (POR) is to expand research and training in inherited metabolic liver diseases (IMLDs), using Gaucher disease (GD) and Wilson disease as index diseases at Yale School of Medicine. The candidate Pramod K. Mistry, MB BS, PhD., an Associate Professor of Medicine, is a respected clinical investigator with unique training and research experience in GD. This proposal will enable Dr. Mistry to expand his current research efforts and to develop a mentoring program that focuses on IMLDs at Yale's Liver Center integrating clinical, laboratory, genetic and epidemiologic approaches. The proposed research project is a continuation of Dr Mistry's ongoing POR. Specific aims are: 1. To explore the contribution of genetic variation in macrophage responsiveness to variation of disease severity in GD in N370S homozygous patients. The proposal seeks to investigate association of disease severity with functional polymorphisms in genes encoding the cytokines that are elevated in GD: Macrophage migration inhibitory factor (MIF), IL 6, IL 10, TNF alpha and TGF beta. 2. To evaluate two further candidate modifier genes for their contribution to a specific phenotype of type 1 GD/severe pulmonary hypertension. Thus, type 1 GD patients with severe PH will be examined for mutations in components of TGF-beta signaling pathway: BMPRII (bone morphogenetic protein receptor II) and ALK1 (activin receptor-like kinase 1). The goals of the mentorship program are to develop scholarship and technical skills in trainees to conduct meritorious POR in IMLDs. The training program consists of a core curriculum, an individualized didactic component in methods of clinical and translational research and an intensively supervised research project in POR. This training program is supported by Liver T32 DK 07356.